Cellular cardiomyoplasty (CCM), which involves the transplantation of exogenous cells into the heart, is a promising approach to repair injured myocardium and improve cardiac function. We have isolated a population of muscle-derived stem cells (MDSCs) from the skeletal muscle of mice and humans, that when compared with myoblasts, display a significantly improved capacity for cardiac regeneration in a mouse model of acute myocardial infarction (AMI). Transplanted MDSCs survive significantly better than skeletal myoblasts due to their high expression of cellular antioxidants, which confers the cells with an increased resistance to stress, and through a paracrine effect which reduces myocardial fibrosis, promotes angiogenesis, and ameliorates left ventricular (LV) remodeling. We have successfully expanded human MDSCs, to clinically relevant numbers in culture and more importantly, human MDSCs have already entered the clinical arena for the treatment of bladder dysfunction & myocardial infarction, confirming that MDSCs represent a viable therapeutic cell source for CCM. However, several limitations, such as a poor delivery approach of the cells (direct intramyocardial injection in PBS) that leads to limited cell retention and survival as well as the low cardiomyogenic potential of the MDSCs, may still limit the cardiac regenerative potential of the MDSCs (Primary focus of the application). The use of FGF2-coacervate, as a novel delivery vehicle for the MDSCs, represents a new area of research that could not only promote cell retention, survival, and the cardiac regenerative potential of the MDSCs, but also synergistically enhance angiogenesis through the release of FGF2. We have shown that coacervate loaded with FGF2 was capable of enhancing cardiac repair and regeneration through the promotion of angiogenesis and supporting the survival of residual cardiomyocytes (preliminary data). Therefore, the focus of Aim 1 of this proposal will be to combine the new FGF2-coacervate technology with MDSCs to further improve cardiac repair. We will compare this combinatorial therapy to MDSCs and FGF2- coacervate therapies separately. Moreover, we have observed that the viral transduction of MDSCs with Wnt- 11, a molecule required for cardiogenesis, enhances the cardiomyogenic differentiation of the MDSCs in vitro and cardiac repair in vivo when injected directly into injured myocardium. In a second set of experiments (Aim 2), we will determine whether the intramyocardial injection of Wnt-11 transduced MDSCs (Wnt-11 MDSCs) in combination with FGF2 coacervate, can further enhance the cardiac regenerative potential of the Wnt-11 MDSCs when compared to non-transduced MDSCs and Inducible Pluripotent Stem Cell (iPSC)- derived cardiomyocytes delivered with FGF2-coacervate. The successful completion of these aims will increase our understanding of the basic biology of muscle-derived progenitor cell populations with enhanced cardiomyogenic potential for cardiac repair and facilitate the development of new therapeutic technologies that merge the merits of stem cell therapy with biomimetic coacervate to improve cardiac repair and regeneration.